• Log in with Facebook Log in with Twitter Log In with Google      Sign In    
  • Create Account
  LongeCity
              Advocacy & Research for Unlimited Lifespans

Photo
* * * * * 2 votes

Cyclodextrins and atherosclerosis

plaque atherosclerosis cyclodextrin cardiovascular disease

  • Please log in to reply
222 replies to this topic

#1 Richard McGee

  • Guest
  • 79 posts
  • 39
  • Location:South Texas

Posted 27 July 2017 - 11:12 PM


This is a thread intended to centralize information regarding the use of cyclodextrin as a potential treatment for atherosclerosis. 
 
I'd like to quote selected material from a 2016 dissertation entitled Targeting cholesterol crystals in atherosclerosis with cholesterol solubilizing 2-hydroxypropyl-β-cyclodextrin. This should serve as a suitable introduction to the subject.
 
"...While elevated blood cholesterol levels have long been considered a risk factor for atherosclerosis, the pathogenic role of crystalline cholesterol, which accumulates in the arterial intima during atherogenesis, has only recently been identified. CCs potently induce innate inflammatory responses, and are considered responsible for the underlying vascular inflammation driving atherosclerosis development and progression. However, so far it has not been investigated whether decreasing the amount of CCs in atherosclerotic plaques is a valuable strategy for pharmaceutical intervention in atherosclerosis. Therefore, this study investigated the potential of the cholesterol solubilizing and mobilizing compound 2-hydroxypropyl-β-cyclodextrin (CD) to remove vascular CCs and thereby prevent murine atherosclerosis development and progression...Cyclodextrins are cyclic oligosaccharides of natural origin. They are generated from the enzymatic degradation of starch by cyclodextrin glycosyltransferases. These bacterial enzymes are closely related to α-amylases, but have the unique ability to catalyze the cyclization of six to eight α-(1,4)-linked D-glucopyranose units. This enzymatic reaction produces the three main cyclodextrins: α-, β- and γ-cyclodextrin, which contain six, seven or eight glucose units, respectively.
 
...The oral bioavailability of pharmaceutically interesting cyclodextrins is generally below 4%, which is mainly due to their high molecular weight and their hydrophilic character, which impedes their ability to cross biological membranes and accordingly their absorption from the gastrointestinal tract. However, once absorbed, any intact cyclodextrin subsequently distributes to various tissues including the kidney, adrenal gland, urinary bladder, liver, but most of it accumulates in the kidney. Cyclodextrins disappear from the tissues quite quickly after administration (within the first few hours) and the intact cyclodextrins are excreted via the urine. Similarly, intravenous administration of cyclodextrins results in rapid renal excretion of the unmetabolized cyclodextrin molecules with nearly 100% recovery in the urine...
 
...oral administration of most cyclodextrins is well tolerated, the parenteral administration of some cyclodextrins, in particular parent α- and β-cyclodextrins can cause problems like renal toxicity. However, some cyclodextrin derivatives, especially hydroxypropylated β-cyclodextrin, have less toxic side effects and are therefore safer for biomedical use than their parent cyclodextrins...In humans, the oral bioavailability of CD ranges from only 0.5 to 3.3%. Approximately half of the orally administered dose is excreted as intact CD via the feces, while the remaining CD is metabolized in the colon by bacterial enzymes. When CD is intravenously administered to humans, it is rapidly excreted from the body as intact, non-metabolized CD molecules into the urine. CD has a small volume of distribution (i.e. the ratio of administered amount to plasma concentration), indicating that CD is not considerably distributed into the tissues. The biological half-life of CD is less than 2 hours and mainly depends on the glomerular filtration rate. Therefore, in individuals with normal kidney function, about 90% of the intravenously administered dose is excreted via the urine within 6 hours, and about 99% within 12 hours post administration (Fig. 2-6). Consequently, parenteral administration of CD will not result in considerable accumulation of CD in individuals with normal kidney function...
 
...Several studies have highlighted the contribution of crystalline cholesterol to the development, progression and clinical outcomes of atherosclerosis. CCs play a role in late stages of the disease where they physically disrupt the fibrous cap promoting plaque rupture and thrombus formation, thereby initiating the acute clinical events. Moreover, CCs induce inflammatory responses by activating the NLRP3 inflammasome. This already happens in early atherosclerotic plaques and is likely to contribute to disease progression108. However, so far it has not been investigated whether decreasing the amount of CCs in the plaque represents a valuable strategy for pharmaceutical intervention in atherosclerosis...
 
...CD is known to mediate the removal of cholesterol from cells and its potential pharmacological use in atherosclerosis as a shuttle for cholesterol mobilization from atherosclerotic plaque tissue to serum lipoproteins such as HDL for increased RCT was already proposed nearly 20 years ago. However, the ability of CD to clear cholesterol from atherosclerotic plaque tissue in the walls of blood vessels has not yet been investigated...
 
...The atherosclerosis mouse models showed that CD has beneficial effects on atherosclerosis development and is even efficient in mediating the regression of atherosclerotic plaques. However, the underlying molecular mechanisms of CD-mediated atheroprotection remained unclear. The finding that decreased murine atherosclerosis was accompanied with a reduction in crystalline cholesterol in the plaques supported the hypothesis that CD’s cholesterol solubilizing capacities might contribute to its anti-atherogenic properties...
 
...CD treatment of CC-loaded macrophages promotes the intracellular esterification and storage of crystalderived cholesterol. macrophages alone are able to dissolve CCs to a low extent and to export the crystal-derived cholesterol out of the cells. This basal efflux of crystal-derived cholesterol was significantly increased at 24 hours when macrophages were treated with CD. However, longer CD treatment did not further increase D6-cholesterol efflux from the macrophages suggesting that the maximum CD-mediated cholesterol efflux capacity is reached at 24 hours...
 
... Export of free cholesterol from macrophages is primarily mediated by the cholesterol efflux transporters ABCA1 and ABCG1, which transfer the cholesterol to ApoA-1 or HDL particles, respectively...CD mediates the dissolution of intracellular CCs and subsequently promotes esterification for intracellular storage as well as efflux of crystal-derived cholesterol. Free cholesterol can be further metabolized to other bioactive derivatives...
 
...CD-mediated efflux of crystal-derived cholesterol could also be further enhanced by addition of rHDL indicating active export of crystal-derived cholesterol via the cholesterol efflux transporters ABCA1 and ABCG1...
 
It was observed that CD treatment results in LXR-dependent upregulation of macrophage cholesterol efflux transporters and facilitates the export of crystal-derived cholesterol from macrophages in vitro. To determine whether this could also occur in vivo, RCT and excretion of crystal-derived cholesterol was monitored in mice...
 
...Almost no D6-cholesterol was detected in the feces of vehicle-treated mice [note: control group]. In contrast, large amounts of crystal-derived D6-cholesterol were excreted via the feces six hours after the first CD treatment of mice injected with D6‑CC-loaded WT BMDMs...Urinary excretion of crystal-derived D6-cholesterol from CD-treated mice injected with D6‑CC-loaded WT BMDMs peaked at approximately nine hours after the first CD injection and again at approximately 18 hours after the first CD injection (two hours after the second CD injection)...
 
...The findings presented in the previous chapters led to the hypothesis that CD might exert its beneficial effects on murine atherosclerosis by dissolving plaque CCs and promoting the production of the endogenous LXR agonist 27-HC. Subsequent activation of LXR transcription factors would induce the expression of cholesterol efflux transporters and thus facilitate removal of cholesterol from the tissue and ultimately the whole body.
Simply switching from atherogenic to chow diet significantly reduced the amount of CCs in the plaques as compared to the pretreatment control. This diet-induced CC reduction could be directly correlated to a reduction of serum cholesterol levels upon diet change and indicates the reversibility of CC deposition in diet-induced murine atherosclerotic plaques. However, the diet change did not reverse atherosclerotic plaque size. In contrast, CD treatment in both regression models (with or without diet change) reduced the amount of existing CCs in the plaques while also mediating a reduction in plaque size, even under continuous feeding of the atherogenic diet...
 
...Altogether these studies indicate that CCs represent a viable treatment target in atherosclerosis and that reducing the amount of CCs in atherosclerotic plaques by genetic or pharmacological means can indeed impede atherogenesis. CD in particular was able to both prevent vascular CC deposition and remove pre-existing CCs from atherosclerotic plaque tissues, and was therefore effective in mediating atherosclerosis regression..."
[bolding is mine]
 
Open issues:
1) Is it sufficiently safe for humans to self-administered CD?
2) Oral versus subcutaneous adminstration
3) Ototoxicity and nephrotoxicity
4) Dosing levels
5) Particular molecular form of cyclodextrin
6) Availability and purity
 
My reading of this paper is that a short-course of intravenous CD might be effective, while avoiding toxicities.
 

Edited by Richard McGee, 28 July 2017 - 12:01 AM.

  • WellResearched x 1

#2 Richard McGee

  • Topic Starter
  • Guest
  • 79 posts
  • 39
  • Location:South Texas

Posted 28 July 2017 - 12:19 AM

Cyclodextrin promotes atherosclerosis regression via macrophage reprogramming

 

Hydroxy Propyl-Beta-Cyclodextrin

 

Hearing Loss and Hair Cell Death in Mice Given the Cholesterol-Chelating Agent Hydroxypropyl-β-Cyclodextrin

 

Preclinical Reversal of Atherosclerosis by FDA-Approved Compound that Transforms Cholesterol into an Anti-Inflammatory “Prodrug”

 

Cyclodextrin Dissolves Cholesterol Crystals So They Can Be Excreted by Body; Reduces Arterial Wall Inflammation

 



sponsored ad

  • Advert
Click HERE to rent this advertising spot for SUPPLEMENTS (in thread) to support LongeCity (this will replace the google ad above).

#3 Richard McGee

  • Topic Starter
  • Guest
  • 79 posts
  • 39
  • Location:South Texas

Posted 28 July 2017 - 01:18 AM

Cyclodextrin appears to be readily available. The particular molecule cited in the OP study is 2-hydroxypropyl-β-cyclodextrin.

 

It is available in powder form on Amazon:

500 gm pharmaceutical grade for $140

100 gm pharmaceutical grade for $45

 

Autoject 2 Self Inject Device 

Description: "Autoject 2 is an advanced auto-injector device that encourages patient self-reliance and helps improve medicine adherence by making subcutaneous injections simple, convenient and more manageable. The ergonomic, easy-to-use design allows many people, especially children and older patients, to self-inject and effectively manage their condition. Can be activated by one-handed operation, making it possible to use a wider range of injection sites than by manually injecting with only a syringe. It also features a protective cap and locking mechanism to control activation and a large viewing window for easy scrutiny of the syringe. Audible and visual indicators at the start and end of dose delivery ensure medication is administered correctly."

 

You would need to determine how to prepare the powder in liquid form for injection. Personally, I'd be very hesitant to undertake the injection method without some solid advice on dosing and frequency. I'm not overly concerned with ototoxicity for one or two injections, but I'd be very reluctant to do more than that.

 

The oral route is probably safer, but I don't know how much would actually be getting into your bloodstream.

 

I'm not recommending anybody actually do this. I'm just pointing out that it's not impossible and that the substance is actually available.



#4 Daniel Cooper

  • Member, Moderator
  • 2,038 posts
  • 425
  • Location:USA

Posted 28 July 2017 - 01:50 AM

Here's two more for consideration.

 

The first is a study were they test α-cyclodextrin given orally for it's effect on blood lipid profiles.  We're not interested in the results of that too much (though they did manage to affect LDL particle sizes which might be important in the process of atherosclerosis) but I think we're more interested in the fact that they were able to achieve useful blood plasma levels via the oral route and they had little in the way of side effects - a few had upset stomach. But keep in mind, this is the α form.

 

Randomized double blind clinical trial on the effect of oral α-cyclodextrin on serum lipids

 

And a second study where they looked at the optimal oral dose for anti-atherosclerosic effects in humans using a mouse model.

 

Cyclodextrins as potential human anti-atherosclerotic agents. A comparative study to determine the optimum route of administration of Hydroxy-propyl-betacyclodextrin in the apolipoprotein-E deficient mouse Part I

 

Cyclodextrins as potential human anti- atherosclerotic agents. A comparative pilot study to determine the most optimum route of of administration of Hydroxy-propyl-ßcyclodextrin (HP-ß-CD) in the apolipoprotein-E deficient 'knockout' mouse: Part III. Determining the optimum concentration of oral HP-ß-CD

 

This is the β form and again, they are looking at oral administration.

 

 

 

 


Edited by Daniel Cooper, 28 July 2017 - 02:01 AM.


#5 Daniel Cooper

  • Member, Moderator
  • 2,038 posts
  • 425
  • Location:USA

Posted 28 July 2017 - 03:01 AM

Just for reference purposes, the FDA GRAS (Generally Recognized As Safe) letter for β-Cyclodextrin:

 

FDA Notice of a GRAS Exemption for Beta-Cyclodextrin

 

 

 



#6 Richard McGee

  • Topic Starter
  • Guest
  • 79 posts
  • 39
  • Location:South Texas

Posted 28 July 2017 - 05:23 AM

Here's two more for consideration.

 

The first is a study were they test α-cyclodextrin given orally for it's effect on blood lipid profiles.  We're not interested in the results of that too much (though they did manage to affect LDL particle sizes which might be important in the process of atherosclerosis) but I think we're more interested in the fact that they were able to achieve useful blood plasma levels via the oral route and they had little in the way of side effects - a few had upset stomach. But keep in mind, this is the α form.

 

Randomized double blind clinical trial on the effect of oral α-cyclodextrin on serum lipids

 

And a second study where they looked at the optimal oral dose for anti-atherosclerosic effects in humans using a mouse model.

 

Cyclodextrins as potential human anti-atherosclerotic agents. A comparative study to determine the optimum route of administration of Hydroxy-propyl-betacyclodextrin in the apolipoprotein-E deficient mouse Part I

 

Cyclodextrins as potential human anti- atherosclerotic agents. A comparative pilot study to determine the most optimum route of of administration of Hydroxy-propyl-ßcyclodextrin (HP-ß-CD) in the apolipoprotein-E deficient 'knockout' mouse: Part III. Determining the optimum concentration of oral HP-ß-CD

 

This is the β form and again, they are looking at oral administration.

 

In the oral study of HP-ß-CD they offer the following conclusion: 

 

the optimum dose rate of HP-ß-CD was 13 mg/mouse/day, the criteria being, the highest dose rate achieved resulting in the highest plasma CD levels without any clinically significant effects on animal health or welfare. Thus it may be concluded that the administration of HP-ß-CD at dose rates of 2.6mg, 5.2mg and 13.0 mg/mouse/day was safe for in-vivo use in female, 9 week-old apoE-deficient ‘knockout’ mice

 

So what would an equivalent dose of 13 mg/day be for a human? The mice weighed an average of 26.5 gms. Is it OK to scale-up in a linear fashion, using a constant dose per body weight, independent of species? If the answer is yes, I make the following calculation:

 

For a 100 kg human, 100/.0265 X 13 = 49056 mg. Or right at 50 gm/day. So, let's say 500 mg/kg? However, this doesn't seem comparable to the 6 gm/day dosage used in the oral α-cyclodextrin study - it's different by a factor of 10. If we go with the lowest dose in the HP-ß-CD study (2.6 mg), the human equivalent would be 100 mg/kg (again assuming linear scaling).

 

Can someone double-check this calculation? I'm not sure I can compare across species this way.


Edited by Richard McGee, 28 July 2017 - 05:45 AM.


#7 aconita

  • Guest
  • 1,389 posts
  • 286
  • Location:Italy
  • NO

Posted 28 July 2017 - 07:14 AM

Oral betacyclodextrin acceptable daily intake is 5mg/kg for humans, it makes about 400mg/day, likely too small an amount for any significant effect given that claimed biovailability is less than 1%, parenteral  is out of question because nephrotoxicity.

 

The mechanism of this kidney toxicity is not entirely clear but seems to be the result of accumulation either of crystals of etacyclodextrin, or insoluble cholesterol - betacyclodextrin complex. It has also been suggested that the nephrotoxicity could be the result of haemolysis.

 

Parenteral is only recommended with pyrogen free hydroxypropyl betacyclodextrins, the literature concerning the parenteral safety profile of HPBCD includes the parenteral infusion of HPBCD on human volunteers with doses up to 470 mg/kg/day, 30 g over 4 days, and IV infusion of single doses of up to 3.0 g.

 

Pyrogen free HPBCD is available but not sure how easy it would be for privates to get it.


  • like x 1

#8 Daniel Cooper

  • Member, Moderator
  • 2,038 posts
  • 425
  • Location:USA

Posted 28 July 2017 - 01:30 PM

Oral betacyclodextrin acceptable daily intake is 5mg/kg for humans, it makes about 400mg/day, likely too small an amount for any significant effect given that claimed biovailability is less than 1%, parenteral  is out of question because nephrotoxicity.

 

The mechanism of this kidney toxicity is not entirely clear but seems to be the result of accumulation either of crystals of etacyclodextrin, or insoluble cholesterol - betacyclodextrin complex. It has also been suggested that the nephrotoxicity could be the result of haemolysis.

 

Parenteral is only recommended with pyrogen free hydroxypropyl betacyclodextrins, the literature concerning the parenteral safety profile of HPBCD includes the parenteral infusion of HPBCD on human volunteers with doses up to 470 mg/kg/day, 30 g over 4 days, and IV infusion of single doses of up to 3.0 g.

 

Pyrogen free HPBCD is available but not sure how easy it would be for privates to get it.

 

Where does that 5mg/kg number come from?  From the GRAS numbers?  If so, that is a dose at which nobody is worried about any side effects without doing any real studies.

 

ETA:  I looked at the FDA GRAS numbers.  Let's consider pudding (no seriously ;) ).

 

The FDA allows a pudding to contain up to 1% β-cyclodextrin by weight.  Pudding is sold in 3.4 oz packets in the US.  That's about 96 grams.  That means your pudding might contain 0.96 grams of β-cyclodextrin.  Surely the FDA considered that you might eat the whole pudding.  So they were apparently confident that 960mg of β-cyclodextrin was safe enough to give it a GRAS exemption.

 

 

 


Edited by Daniel Cooper, 28 July 2017 - 02:05 PM.


#9 Daniel Cooper

  • Member, Moderator
  • 2,038 posts
  • 425
  • Location:USA

Posted 28 July 2017 - 01:40 PM

 

So what would an equivalent dose of 13 mg/day be for a human? The mice weighed an average of 26.5 gms. Is it OK to scale-up in a linear fashion, using a constant dose per body weight, independent of species? If the answer is yes, I make the following calculation:

 

For a 100 kg human, 100/.0265 X 13 = 49056 mg. Or right at 50 gm/day. So, let's say 500 mg/kg? However, this doesn't seem comparable to the 6 gm/day dosage used in the oral α-cyclodextrin study - it's different by a factor of 10. If we go with the lowest dose in the HP-ß-CD study (2.6 mg), the human equivalent would be 100 mg/kg (again assuming linear scaling).

 

Can someone double-check this calculation? I'm not sure I can compare across species this way.

 

 

 

So, they have their mouse weights in the paper and I want to say they were about 18 grams.  I came out with 13mg/0.018kg = 722mg/kg.  The generally accepted conversion factor to go from mice to man is 1/12. So, in a man 722mg/12 = 60mg/kg.  For a 77kg man that would be 4,634 mg or 4.6 grams.

 

We have a human trial above where they dosed the α form of cyclodextrin at 6g/day orally.  I have a paper with some indication that the β form is less ototoxic in humans than the α form.  I'll try to post it this evening.


Edited by Daniel Cooper, 28 July 2017 - 02:13 PM.


#10 Daniel Cooper

  • Member, Moderator
  • 2,038 posts
  • 425
  • Location:USA

Posted 28 July 2017 - 01:45 PM

BTW guys, what we need to look at is what is coming out of the people being treated for Niemann Pick's.  I was under the impression that all NP patients were being treated intrathecally, since the compound doesn't cross the BBB.  Surprisingly, some NP patients are being dosed IV.  Surprises the heck out of me but it's true.  If we can find what issues those patients are having we would have a good handle on what to be worried about, because those patients are certainly getting significant doses of βCD.

 

 

 



#11 Daniel Cooper

  • Member, Moderator
  • 2,038 posts
  • 425
  • Location:USA

Posted 28 July 2017 - 02:22 PM

More info from the GRAS letter - 

 

 

Assuming replacement of all encapsulating Appendix 1 Page 5 agents/protectants with p-CD (21 C.F.R. 5 172.230), the estimated exposure of the total population to p-CD from the above listed food categories would be 1.44 mgkg body weighdday' for the 90th percentile consumer (eaters only). When used at levels of up to 2%, as specified here, this intake level would approach the JECFA AD1 of 5 mg/kg body weighdday. Given that (1) the use of encapsulating agentdprotectants has significantly decreased in recent years (FEMA, 1999) and (2) a safety factor of 100 to was used to establish the ADI, the increased exposure to p-CD from use levels of up to 2% in the above listed food categories does not present a safety concern.

 

This may be the 5mg/kg/day quoted above.  The FDA says they used a safety factor of 100.  It isn't entirely clear to me if that is on the 1.4mg/kg/day or 5mg/kg/day.  Let's be pessimists and assume it is against the lower number and that 144mg/kg/day would the safe level with out their 100x margin.  That would be 11 grams per day for a 77kg person.

 

 



#12 Richard McGee

  • Topic Starter
  • Guest
  • 79 posts
  • 39
  • Location:South Texas

Posted 28 July 2017 - 05:49 PM

Efficacy and ototoxicity of different cyclodextrins in Niemann–Pick C disease

 

Wt mice used for ABR recordings were given weekly subcutaneous injections of 5.74 mmol/kg body weight of CD (from a 0.286 mol/L solution) or water alone starting at 8 weeks of age...

 

...Although vehicle‐treated mice had thresholds near 40 dB SPL consistent with normal hearing, mice treated with HPβCD had thresholds ≥100 dB SPL, indicative of extreme hearing loss (Fig. (Fig.5A,5A, B). Nearly half the mice treated with HPγCD had a threshold at 88 dB SPL, while all other groups (SBEγCD, SBEβCD, HPαCD) had normal thresholds. Importantly, these trends persisted across the three time points spanning 20 weeks of treatment (Fig. S2). In all cases, mean hearing thresholds were statistically significantly higher for HPβCD‐treated mice than for any other group and no significant differences existed between vehicle‐treated and SBEγCD, SBEβCD, or HPαCD‐treated mice (Fig. (Fig.5C).5C). Thresholds for HPγCD‐treated mice were intermediate between normal hearing and extreme hearing loss.

 

This is troubling. We don't know how much orally-administered beta-cyclodextrin ends up circulating in human plasma. We don't know how much will make its way to cochlear hair cells. There may be a threshold below which beta-CD doesn't cause permanent hearing loss, but we don't know where that threshold is (at least in terms of oral dosing). The alpha human study was 6 grams/day, 12-14 weeks, with 75 patients completing the study. There was no mention of ototoxicity.

 

The more I look at it, the more I think we should take the HPβCD molecule (and probably the HPγCD variant, as well) off our list of potential candidates - at least until we know more about how orally administered HPβCD affects humans. 

 


Edited by Richard McGee, 28 July 2017 - 05:53 PM.


#13 Daniel Cooper

  • Member, Moderator
  • 2,038 posts
  • 425
  • Location:USA

Posted 28 July 2017 - 06:47 PM

Efficacy and ototoxicity of different cyclodextrins in Niemann–Pick C disease

 

Wt mice used for ABR recordings were given weekly subcutaneous injections of 5.74 mmol/kg body weight of CD (from a 0.286 mol/L solution) or water alone starting at 8 weeks of age...

 

...Although vehicle‐treated mice had thresholds near 40 dB SPL consistent with normal hearing, mice treated with HPβCD had thresholds ≥100 dB SPL, indicative of extreme hearing loss (Fig. (Fig.5A,5A, B). Nearly half the mice treated with HPγCD had a threshold at 88 dB SPL, while all other groups (SBEγCD, SBEβCD, HPαCD) had normal thresholds. Importantly, these trends persisted across the three time points spanning 20 weeks of treatment (Fig. S2). In all cases, mean hearing thresholds were statistically significantly higher for HPβCD‐treated mice than for any other group and no significant differences existed between vehicle‐treated and SBEγCD, SBEβCD, or HPαCD‐treated mice (Fig. (Fig.5C).5C). Thresholds for HPγCD‐treated mice were intermediate between normal hearing and extreme hearing loss.

 

This is troubling. We don't know how much orally-administered beta-cyclodextrin ends up circulating in human plasma. We don't know how much will make its way to cochlear hair cells. There may be a threshold below which beta-CD doesn't cause permanent hearing loss, but we don't know where that threshold is (at least in terms of oral dosing). The alpha human study was 6 grams/day, 12-14 weeks, with 75 patients completing the study. There was no mention of ototoxicity.

 

The more I look at it, the more I think we should take the HPβCD molecule (and probably the HPγCD variant, as well) off our list of potential candidates - at least until we know more about how orally administered HPβCD affects humans. 

 

I think you want to be very cautious.  I'm not putting anything in my body until I'm 99.9999% sure it's safe.  But a 5.74mmol/kg solution is actually pretty strong.  I doubt you're going to get anywhere near the final plasma concentrations that they are achieving in those mice through oral administration.  I've been looking at this for some time now and I swear I saw a paper that studied the blood plasma levels achievable via oral administration and they were quite low, on the order of a few nmol (I wish I could find this paper btw). In fact, I had pretty much forgotten about βCD because I wasn't interested in injecting it and didn't think you could do anything useful via the oral route.  Subsequent papers have made me reconsider.

 

Also, if you'll notice figure 5 in that paper there were some variants of CD that were significantly less ototoxic.  I actually had it backwards, the alpha form was better in this regard than the beta.

 

This is after all a compound that is used in foodstuffs and is on the GRAS list, albeit at lower quantities.

 

What I'd really like to do is find a paper or talk to a doc that is treating NP patients with IV βCD.  If they are not seeing ototoxic effects then I can't imagine you'd ever have to worry about that with oral administration.  You're never going to achieve the plasma levels that they are getting via the oral route.

 

I'm going to keep looking at this but I'm not about to pull the trigger.

 

 


Edited by Daniel Cooper, 28 July 2017 - 06:51 PM.


#14 Daniel Cooper

  • Member, Moderator
  • 2,038 posts
  • 425
  • Location:USA

Posted 28 July 2017 - 07:33 PM

Ah, now we're getting somewhere.  A review of toxicology studies, including studies with human subjects with doses as high as 24g/day for 14 days. Also various animal studies.

 

2-Hydroxypropyl-b-cyclodextrin (HP-b-CD): A toxicology review

 

 

 

 

 

 



#15 Daniel Cooper

  • Member, Moderator
  • 2,038 posts
  • 425
  • Location:USA

Posted 28 July 2017 - 07:44 PM

More cyclodextrin safety info.  This time from the European Medicines Agency.

 

Background review for cyclodextrins used as excipients

 

Relevant passage:

 


 

All parent cyclodextrins are accepted as food additives and “generally recognized as safe” (GRAS). As dietary supplement the total daily oral dose of α-CD may reach 6000 mg/day, for β-CD 500 mg/day and for γ-CD 10 000 mg/day, and for HP-β-CD as oral pharmaceutical 8000 mg/day [22]. Preclinically, oral NOELs after a year of HP-β-CD are 500 mg/kg/day for rats and 1000 mg/kg/day for dogs [12]. Oral NOAELs of SBE-β-CD in rats and dogs after 3 months are both 3600 mg/kg/day [27]. RM-β-CD has no oral application.

 

 



#16 aconita

  • Guest
  • 1,389 posts
  • 286
  • Location:Italy
  • NO

Posted 28 July 2017 - 09:37 PM

Now that you convinced yourself my numbers are correct we can move on.

 

The only CD worth attention is HPBCD, oral bioavailability might be a bit better since water solubility is much better which

 

it is one of the two hindering factors (the other being the high molecular weight which in HPBCD is higher than in CD but likely negligibly so for our purpose).

 

It would be interesting to find some paper about how much HPBCD is bioavailable for oral route, otherwise I can see only the IV as worth.

 

HPBC  aren't all the same either, they come at different degrees of substitution as described by
the MS value

 

The MS value (average molar degree of substitution) is the average number of moles of hydroxypropyl groups per anhydroglucopyranose unit.

 

Pyrogen free is another factor to consider if parenteral route is chosen.

 

I wouldn't be so comfortable with the amazon product linked above, the sellers seems targeting make your own cosmetics customers, likely Chinese production, no much info available.

 

http://www.lelworld....-cyclodextrin/ 



#17 Daniel Cooper

  • Member, Moderator
  • 2,038 posts
  • 425
  • Location:USA

Posted 28 July 2017 - 09:44 PM

Now that you convinced yourself my numbers are correct we can move on.

 

 

If by your numbers you mean the 5mg/kg dose limit I'm now fairly convinced your numbers are indeed wrong.  The European Medicines Agency says the daily dose limit for HPβCD is 8000mg/day.  And I have a toxicology review citing a study in humans at 24g/day.

 

See my prior two posts above.

 


 



#18 aconita

  • Guest
  • 1,389 posts
  • 286
  • Location:Italy
  • NO

Posted 28 July 2017 - 10:27 PM

Did you get the difference between CD and HPBCD?

 

Well 5mg/kg is about CD, as well specified in my post.

 

Aceptable Daily Intake (ADI) J.E.C.F.A. (February 1995) and the European scientific Committee for Foods (SCF, December (1996) evaluated the betacyclodextrin and assigned it an ADI of 5 mg/kg bodyweight.

 

Which for an 80kg individual is about 400mg/day. 

 

HPBCD is a whole another ballgame with values much higher, as well specified.

 

We aren't turning this thread too in a boring confrontation about whom is right like the "reversing arterial plaque" one, aren't we?

 

The point isn't about how many mg more or less, converting useless rat studies numbers into humans and such, or assuming safety tolerance margins given by different authorities to be ignored or re-interpreted to fit our wishes.

 

CD isn't worth attention for our scope since not suitable for parenteral, very poor bioavailability and toxicity which limits even the oral intake to such an extent any plaque reduction would be very unlikely, regardless ignoring safety limits or not.

 

The only worth consideration is HPBCD in humans which has been proven reasonably safe at amounts far exceeding any practical use, lets focus there.

 

Now the main question is: is HPBCD feasible by oral route because bioavailability is good enough or parenteral is the only viable option?



#19 Daniel Cooper

  • Member, Moderator
  • 2,038 posts
  • 425
  • Location:USA

Posted 28 July 2017 - 10:50 PM

Did you get the difference between CD and HPBCD?

 

 

Ah, yes I did not notice that. I've assumed that we were mainly talking about HPβCD.  I agree, the βCD version is not interesting for our purpose.

 

With respect to the ability to obtain high enough plasma levels via oral delivery, look at my first post in this thread. The second set of papers in that post are to a mouse study where they looked to see if they could achieve an anti-atherosclerotic effect with oral administration.  They were able to do so.  Unless bioavailability is significantly different between mice and men (which is possible) then it looks like you can take enough HPβCD to be useful. If my math is right and the normal 1/12 factor applies to go from a mouse dose to a man dose, their effective dose translates to about 4.6g/day in a 77kg man.  Since I am only 62kg, I'd probably take 4g/day.

 

-Dan


Edited by Daniel Cooper, 28 July 2017 - 10:51 PM.


#20 aconita

  • Guest
  • 1,389 posts
  • 286
  • Location:Italy
  • NO

Posted 28 July 2017 - 11:25 PM

Cool, now we are on track!

 

I don't believe much in animal studies because there are already enough differences between humans without bothering with those between us and animals too, but anyway it could be a start.

 

I haven't gone thru all the studies linked yet (my fault and I apologize), I'll do in this weekend and maybe attempt some more research on the subject myself.

 

A source for quality HPBCD could be Kleptose HPB by Roquette.

 

https://www.roquette...n-bcd-hpbcd.pdf

 

First half is about CD, second half about HPBCD, quite an interesting reading (and source for some of my numbers/info).

 

At the end all countries representatives, US included.



#21 Richard McGee

  • Topic Starter
  • Guest
  • 79 posts
  • 39
  • Location:South Texas

Posted 29 July 2017 - 01:32 AM

To summarize, the HPβCD variant of cyclodextrin is the one particular molecule shown to mediate the dissolution of intracellular CCs (cholesterol crystals) and subsequently promote esterification for intracellular storage as well as efflux of crystal-derived cholesterol. It would appear to be the main substance of interest for substantial clearing of CCs.

 

At the same time, HPβCD has been singled out as the most ototoxic variant, at least when administered by injection.

 

Some preliminary thoughts/questions:

 

1) α-CD seems to act like other soluble fibers in interfering with triglyceride and cholesterol absorption. This makes it probably not a lot more interesting than Metamucil, as far as I can tell.

2) Injecting HPβCD poses a number of risks. Special care and selection of materials is needed to prepare a non-pyrogenic solution for injection. Special care is needed to not exceed dangerous blood plasma levels of HPβCD. My assessment is that it would be too dangerous; at least, too dangerous for me.

3) Oral administration of HPβCD at recognized safe levels is the most conservative alternative.

4) For humans, a dose in the range of 60 mg/kg/day appears to be well within the safe range. This would translate to 6 gms for a 100 kg individual, for example.

5) What level of purity would be sufficient for oral administration? Pharmaceutical grade? Food grade?

 

 

 



#22 Daniel Cooper

  • Member, Moderator
  • 2,038 posts
  • 425
  • Location:USA

Posted 29 July 2017 - 02:07 AM

Richard,

 

I think I basically agree but even injecting the stuff can be done safely.  As they say, the dose makes the poison.  If you look at page 40 of that pdf that aconita posted you'll see the following concerning parenteral administration of HPβCD:

 

Human

Intravenous (acute) Infusion of 5% (w/v) solution - No adverse effects at a rate of 470 mg/kg/day, total dose of 30g over 4 days

 

Intravenous (acute) Infusion at a rate of 100 mg/min. - No adverse effects total doses of 0.5-3 g

 

That is a really substantial IV dose.  We should be very cautious but I'm starting to feel much more comfortable about any oral dose I'm likely to ingest, and even IV administration doesn't scare me as much.  Of course, I'm not about to go do this tomorrow either. 

 

As I said, the dose makes the poison.  After all, the LD50 dose of NaCl is about 200g.  Yet we don't worry about sprinkling it on our food.

 

 


Edited by Daniel Cooper, 29 July 2017 - 02:10 AM.


#23 Daniel Cooper

  • Member, Moderator
  • 2,038 posts
  • 425
  • Location:USA

Posted 29 July 2017 - 02:17 AM

A source for quality HPBCD could be Kleptose HPB by Roquette.

 

https://www.roquette...n-bcd-hpbcd.pdf

 

First half is about CD, second half about HPBCD, quite an interesting reading (and source for some of my numbers/info).

 

At the end all countries representatives, US included.

 

I'm sure that is an excellent quality source for HPβCD.  But, two questions arise -

 

1.) Would they sell it to someone not affiliated with a medical facility or a lab?

 

2.) Could you afford it if they would?

 

I don't know the answer to either of those questions, but I fear the answer to just the first one may be no.

 

 



#24 Richard McGee

  • Topic Starter
  • Guest
  • 79 posts
  • 39
  • Location:South Texas

Posted 29 July 2017 - 03:07 AM

The GRAS notification for beta cyclodextrin recognizes its use in "baked goods prepared from dry mixes, breakfast cereal, chewing gum, gelatins and puddings, dry mix for soups, flavored coffee and tea, compressed candies, processed cheese products, flavored savory snacks and crackers, dry mix for beverages." So basically we are talking about a food product. As long as we are talking about ingesting this substance, I would venture to say that food-grade HPβCD at the amounts we have been talking about (4 - 6 gms/day) would be safe and relatively inexpensive.

 

Note: the CAS Registry Number for 2-hydroxypropyl-beta-cyclodextrin is 128446-35-5. 


Edited by Richard McGee, 29 July 2017 - 03:25 AM.


#25 aconita

  • Guest
  • 1,389 posts
  • 286
  • Location:Italy
  • NO

Posted 29 July 2017 - 04:17 AM

I am not 100% sure but quite so that a few years back I actually contacted Roquette in France and the answer was the classical "sorry, we don't sell to privates".

 

What that means is without a VAT number they don't sell, in other words they don't sell to the public (mainly for fiscal reasons), these aren't restricted products (even the pharma grade for parenteral use), if you have got a VAT (or friend running a business) there should be no problem (but likely a minimum amount).

 

It is a food additive, not a drug... and as a pharmaceutical is a carrier not an active.

 

I doubt it would be overly expensive, one UK seller on eBay offers 100g Kleptose for 10 euro (it is the CD, not the HPBCD, but price difference shouldn't be too big and the seller is making a profit too, of course).

 

The US supplier address is there at the end of the PDF, just ask them, in US fiscal policies are much different than in EU and they might well sell to anybody that side of the pond.

 

One thing is for sure: I wouldn't even consider IV from a doubtful source... and very likely not even oral, for that matter.

 

The question here is still about how biavailable it is as oral.

 

As you can see in the linked PDF for CD is stated less than 1%, we might assume a greater bioavailability for HPBCD due to its much greater water solubility but the high molecular weight bottleneck is still all there...

 

Because if (for example) bioavailability is 1% and 5g oral for an average individual is enough to reduce arterial plaque as IV it might correspond to as little as 50mg, which seems quite safe according to the numbers we got (0,5-3g acute IV infusion) and price at that point would be almost irrelevant considering one wouldn't need to inject everyday 365/year in order to achieve substantial results.

 

I am not pushing the IV route whatsoever, just wondering.

 

Oral would be more pleasant, obviously, and at the same time used as a carrier for something else too.



#26 Kevinsan

  • Guest
  • 26 posts
  • 7
  • Location:US

Posted 07 August 2017 - 07:38 PM

Hate to cross post but here is what we do:

 

Here are some easy ways to clear up that nasty plaque.

 

  1. Lipo EDTA - Commercially available. Wake up at night, take your one or two grams, fall back to sleep. Eat breakfast a few hours later and mineral supplements around noon. Half life is 45 minutes. Takes forty treatments. At two treatments a week it takes five months. Total cost: ~$800 USD. Bit of a flush.
  2. Lipo Trehalose - Make at home with a sonicator. Take daily. Research says 35% plaque reduction in mice. Cheap
  3. Lipo 2 hydroxypropyl Beta cyclodextrin. make at home in a sonicator. Research says 75% plaque reduction. They inject it into the brains of children to reduce plaque so it is perfectly safe. In mice fed obscenely plaque causing diets, the daily dose of HPCD prevented any and all plaque buildup. US made expensive. China made cheap.

Of course all can be injected. But the lipo has added benefits. You can research why. Tried them all. Prefer 1 and 3. Take 3 on a daily basis. For instructions, search DIY Lipo Vitamin C or Glutathione.



#27 thedarkbobo

  • Guest
  • 153 posts
  • 25
  • Location:EU

Posted 09 August 2017 - 03:37 PM

Interesting topic and post by Kevinsan.

 

  • How do we get HPCD in/to Europe?

 

Have checked the DIY Lipo - looks promising, however was it should be checked if:

  • in fact this homemade DYI makes Liposomes (https://www.peakener...omal-nutrients/ states it does not)

     

    All I can say is that the simple ultrasonic treatment of lecithin and vitamin C does not make liposomes. I have reviewed the sophisticated testing of two different such preparations. Both of them: zero liposomes.

    However, the ultrasonic treatment does results in a legitimate emulsion, which is absorbed much better than just regular vitamin C. However, that is just absorption into the blood, not enhanced uptake inside the cells, as with liposomes.

     

  • Liposomal HPCD absorbes properly and reduces plaque

 



#28 Kevinsan

  • Guest
  • 26 posts
  • 7
  • Location:US

Posted 09 August 2017 - 04:46 PM

Thanks for the info Bobo. Time to look into a home extrusion machines. They make simple extrusion syringes with filters for lab use, but I will need a slightly larger model. I remember seeing ones that will do 300ml. Should be fun. No telling what we will make!

 

I get my cyclodextrin here: cyclodex.com/beta-cyclodextrin-food-grade.html


  • like x 1

#29 Kevinsan

  • Guest
  • 26 posts
  • 7
  • Location:US

Posted 09 August 2017 - 08:30 PM

Here is the machine. 150ml max. High pressure through a polycarbonate membrane.

 

Principle of Operation:

The NanoAble-150 uses compressed gas at pressures up to 1000psi/68bar to pressurize the sample cylinder and force the starting materials through a polycarbonate membrane.

 

phdtechintl.com/products_nanoable-150.html

 

Or someone could have it commercially made and sell it on Amazon. Hint Hint. Plenty of companies offer liposomal production services. I'll contact some companies that currently offer liposomal products and see if they can whip up a batch for sale. Companies are always looking for an angle.

 

nanoable-150.jpg

 

 

 



sponsored ad

  • Advert
Click HERE to rent this advertising spot for SUPPLEMENTS (in thread) to support LongeCity (this will replace the google ad above).

#30 thedarkbobo

  • Guest
  • 153 posts
  • 25
  • Location:EU

Posted 09 August 2017 - 09:00 PM

Thanks Kevinsan :)

 

Let me paste some..(sadly most papers are drug-delivery oriented not HP-BCD administration absorption)

https://notendur.hi....tlo/general.pdf

 

 

1) Sublingual
From a toxicological point of view the use of cyclodextrins in sublingual formulations is closely related to other forms of oral administration. The large hydrophilic cyclodextrin mole-
cules do not permeate across the sublingual mucosa and, thus, they are eventually swallowed.
2) Nasal
Only insignificant amounts of cyclo-dextrins are absorbed from the nasal cavity. The local toxicity of cyclodextrins after nasal administration is very low
3) Pulmonary administration
Cyclodextrins are more readily absorbed from the lungs than from the gastrointestinal tract and this limits the 2-hydroxypropyl-β-cyclodextrin complexation (*actually good for us)
A recent study with budesonide also showed that cyclodextrin complexes could be used in an inhalation powder without lowering the pulmonary deposition of the drug
(page 20), need more studies
4) Ophthalmic ...no.
5) Dermal..
(..) only negligible amounts of topically applied hydrophilic cyclodextrins (..).
 
 

 

HPBCD has been administered orally to determine the metabolic fate of the HPBCD Most of the label was excreted in the feces.3-6% of the label was absorbed and some label appeared in the blood about five minutes after administration indicating some absorption from the stomach. About 3% of the label appeared in the urine and another 3.25% in the exhaled CO2.

 

The HPBCD preparation did contain some propylene glycol that was also labeled. The amount of label absorbed corresponded to the amount of propylene glycol present.

This sounds interesting

 

Ah right!

/Many studies have shown that the combination of propylene glycol with fatty acid has exhibited a synergistic effect on absorption enhancement./

 

Hmm no access to full paper

http://pubs.acs.org/...rnalCode=jafcau

 

https://www.ncbi.nlm...les/PMC3124402/

 

 

The microemulsion formulation was optimized using a pseudoternary phase diagram, comprising propylene glycol dicaprylocaprate.

 

Cremophor RH40 (surfactant) and ethanol (cosurfactant) were mixed in a vial at room temperature followed by the addition of PG (oil phase), and then the mixture was blended for 5 minutes until they had completely mixed. The HSYA solution was then added to the mixture and stirred for 3 minutes until a clear and transparent w/o microemulsion was obtained.

(*HSYA is a substance they wanted to carry, not sure if we can substitute RH40 for some other solubilizer/emulsifying agent if it is really needed)

 

http://www.ebay.com/...lene-glycol-usp

 

Anyway 3-6% would not be much I guess..but better than nothing.

 

Well and eye drops would be nice to make.

http://www.sciencedi...014483515001372

 


Edited by thedarkbobo, 09 August 2017 - 09:58 PM.






Also tagged with one or more of these keywords: plaque, atherosclerosis, cyclodextrin, cardiovascular disease

1 user(s) are reading this topic

0 members, 0 guests, 0 anonymous users


    Bing (1)